Tetrahydrofuran → 1-[2-Fluoro-4-(2-phenoxycarbonylaminopyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester

HRID 409935Notes

Reaction equation

HRID 409935 reaction equation
[CH2:1]([O:8][C:9]([C:11]1([C:14](=[O:31])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=3)=[CH:18][C:17]=2[F:30])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.Cl[C:38]([O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:39]>C(#N)C.N1C=CC=CC=1>[CH2:1]([O:8][C:9]([C:11]1([C:14](=[O:31])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:38]([O:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:39])[CH:24]=3)=[CH:18][C:17]=2[F:30])[CH2:12][CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

6

Reactant 3

HCID 8028TetrahydrofuranHCID 15891Phenyl chloroformateHCID 59459707HCID 59459707, compound

Product 1

HCID 247886951-[2-Fluoro-4-(2-phenoxycarbonylaminopyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid benzyl esterYield 4%

Reagents, catalysts & solvents 2

HCID 1049PyridineSolventHCID 6342AcetonitrileSolvent2×

Conditions

Temperature
10 °C

Procedure

1-[4-(2-Aminopyridin-4-yloxy)-2-fluorophenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester (176.0 kg), tetrahydrofuran (1876 kg), acetonitrile (692 kg) and pyridine (860 kg) were mixed and cooled to 10° C. Phenyl chloroformate (105 kg) was added dropwise to the mixed solution over a period of 1 hour at 10° C. The crystals were precipitated while the solution was added dropwise. After completing the dropwise addition, the completion of reaction was confirmed using an HPLC apparatus. Subsequently, acetonitrile (692 kg) was added to the reaction mixture. The crystals were collected by filtration, washed with a mixed solution of tetrahydrofuran (234 kg) and acetonitrile (207 kg) and dried under reduced pressure to give the crude crystals of 1-[2-fluoro-4-(2-phenoxycarbonylaminopyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester (202. 9 kg). The crude crystals (202.9 kg), acetonitrile (638 kg) and water (812 L) were stirred for 1 hour at 20° C. The crystals were collected by filtration, washed with acetonitrile (319 kg) and dried under reduced pressure to give the title compound (174.8 kg). Apparent yield 77.1%, purity 93.9% (HPLC area percentage).

Workup

  1. customThe crystals were precipitated while the solution
  2. additionwas added dropwise
  3. additionthe dropwise addition
  4. customthe completion of reaction
  5. filtrationThe crystals were collected by filtration
  6. washwashed with a mixed solution of tetrahydrofuran (234 kg) and acetonitrile (207 kg)
  7. customdried under reduced pressure

Sources & evidence

ORD record
ord-a99b47a6216c47b6b861711e309a38b7
Source dataset
uspto-grants-2014_06
Patent number
US08759530B2

Reaction notes

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